NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency
Open accessAbstract
Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ +/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ +/− mice have a reduced cerebral NAD + /NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ +/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ +/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ +/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ +/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD + depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD + levels therefore have therapeutic potential for AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NMN and NR protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation.
“NMN and NR demonstrated protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [24]
The Discussion (p. 7) reports that NR improved several Alzheimer-like features, including neuroinflammation, in mouse models; it also cites animal-model findings for NMN and Alzheimer-related outcomes. The paper does not establish protection against diabetes or endothelial dysfunction, and its inflammation finding is specific to neuroinflammation in the Alzheimer mouse models. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNR significantly reduced neuroinflammation, hippocampal neuron apoptosis, phosphorylated Tau, and DNA damage, while increasing neurogenesis by almost 20%.
“Futhermore, NR significantly reduced neuroinflammation, apoptosis of hippocampal neurons, phosphorylated Tau and DNA damage, while also increasing neurogenesis by almost 20% [24].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [24]
The Results (pp. 6–7) report reduced phosphorylated Tau, DNA damage, and apoptosis after NR treatment; the Discussion (p. 7) reports reduced neuroinflammation. The Results (p. 4) also report increased proliferation of neuronal progenitor cells, but our copy does not give an almost-20% increase in neurogenesis. The findings concern AD mouse models and cultured mouse cells, rather than an unqualified effect. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNR protects cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer disease models.
“NR demonstrated protective effects on cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer’s disease models [24, 27].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [24]
NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in an Alzheimer's disease mouse model.
“NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in an AD mouse model [74].”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [74]
AD mouse models with Polβ heterozygosity feature defective DNA repair and show increased synaptic and cognitive deficits, neuronal dysfunction and cell death.
“AD mouse models with Polβ heterozygosity feature defective DNA repair and showed increased synaptic and cognitive deficits, neuronal dysfunction and cell death [502].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [502]
In Alzheimer's disease mouse models, supplementation with NAD+ precursors improves synaptic plasticity and neuronal morphology.
“Supplementation with NAD+ precursors has been shown to improve synaptic plasticity and neuronal morphology in AD mouse models (Fang et al., 2019; Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
In neurons, base excision repair, the main pathway for repairing oxidative DNA damage, is reduced in elderly humans and in Alzheimer's disease patients.
“In neurons, BER, the primary pathway for the repair of oxidative DNA damage, is reduced in elderly humans and in AD patients (Hou et al., 2018; McKinnon, 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
Nicotinamide riboside treatment also improved neurogenesis and proliferation of neural progenitor cells in a BER-defective 3xTg Alzheimer's disease mouse model.
“NR treatment also improved neurogenesis and proliferation of neural progenitor cells in a BER-defective 3xTg AD mouse model (Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
In Alzheimer's disease mouse models, supplementation with the NAD+ precursor nicotinamide riboside inhibited disease-associated neuroinflammation, decreased numbers of activated microglia and astrocytes, and reduced pro-inflammatory cytokines.
“In AD mouse models, supplementation with the NAD+ precursor NR inhibited the disease-associated neuroinflammation, decreased the numbers of activated microglia and astrocytes, and reduced pro-inflammatory cytokines (Fang et al., 2019; Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
In a BER-defective 3xTgAD/Polβ+/− mouse model, nicotinamide riboside supplementation reduced DNA damage, as evidenced by reduced γH2AX staining (marking DNA double-strand breaks) in the hippocampus.
“In a BER-defective 3xTgAD/Polβ+/− mouse model, NR supplementation reduced DNA damage as evidenced by reduced γH2AX staining (marking DNA DSBs) in the hippocampus (Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
In rodent models of early-onset familial Alzheimer's disease, brain NAD+ depletion and metabolic dysfunction have been demonstrated.
“In rodent models of early-onset familial AD, brain NAD+ depletion and metabolic dysfunction have been demonstrated (Dong and Brewer, 2019; Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
NAD+ augmentation inhibited Alzheimer's disease-related pathology and cognitive decline in different AD animal models, including 3xTgAD mice treated with nicotinamide, 3xTgAD/Polβ+/− mice treated with nicotinamide riboside, and neuronal Aβ1-42 and Tau transgenic C. elegans models.
“Accordingly, NAD+ augmentation inhibited AD-related pathology and cognitive decline in different AD animal models, including 3xTgAD mice treated with NAM (Liu et al., 2013), 3xTgAD/Polβ+/− mice treated with NR (Hou et al., 2018), and in neuronal Aβ1–42 and the neuronal Tau (pro-aggregant F3ΔK280 tau fragment) transgenic C. elegans models (Fang et al., 2019) (summarized in Table 1).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
Second, NAD+ augmentation inhibits neuroinflammation in Alzheimer's disease mice.
“Second, NAD+ augmentation inhibits neuroinflammation in AD mice (Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
Third, NAD+ augmentation restores neurogenesis in Alzheimer's disease mice by promoting the proliferation of neural progenitor cells.
“Third, NAD+ augmentation restores neurogenesis in AD mice by promoting the proliferation of neural progenitor cells (Hou et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hou et al., 2018
NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease, and show neuroprotective properties in Drosophila models of Parkinson disease and mouse models of ALS.
“the NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease136,161,175–180, and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease181,182 and in mouse models of ALS139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [175]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232 · see citing works
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069 · see citing works
Morris water maze: procedures for assessing spatial and related forms of learning and memory
Vorhees, C. V., & Williams, M. T. (2006) · Nature Protocols · doi:10.1038/nprot.2006.116 · Cited by 4,629 · see citing works
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Self-citationThe molecular biology of memory storage: a dialogue between genes and synapses
Kandel, E. R. (2001) · Science · doi:10.1126/science.1067020 · Cited by 3,917 · see citing works
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · see citing works
Object recognition test in mice
Leger, M., Quiedeville, A., Bouet, V., Haelewyn, B., Boulouard, M., Schumann-Bard, P., & Freret, T. (2013) · Nature Protocols · doi:10.1038/nprot.2013.155 · Cited by 1,357 · see citing works
NAD <sup>+</sup> in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319 · see citing works
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · see citing works
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., et al. (2016) · Science · doi:10.1126/science.aaf2693 · Cited by 1,255 · see citing works
The Reactome pathway Knowledgebase
Fabregat, A., Sidiropoulos, K., Garapati, P., Gillespie, M., Hausmann, K., Haw, R., Jassal, B., Jupe, S., Korninger, F., McKay, S., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1351 · Cited by 1,201 · see citing works
Tau pathology and neurodegeneration
Spillantini, M. G., & Goedert, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70090-5 · Cited by 1,133 · see citing works
Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms
Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., Bohr, V. A., & Fang, E. F. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.01.002 · Cited by 870 · see citing works
Self-citationSlowing ageing by design: the rise of NAD+ and sirtuin-activating compounds
Bonkowski, M. S., & Sinclair, D. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.93 · Cited by 834 · see citing works
PAGE: Parametric Analysis of Gene Set Enrichment
Kim, S., & Volsky, D. J. (2005) · BMC Bioinformatics · doi:10.1186/1471-2105-6-144 · Cited by 781 · see citing works
Al-Atrache, Z., Cader, A., & Appelt, D. M. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.894 · Cited by 765 · see citing works
Defective Mitophagy in XPA via PARP-1 Hyperactivation and NAD+/SIRT1 Reduction
Fang, E. F., Scheibye-Knudsen, M., Brace, L. E., Kassahun, H., SenGupta, T., Nilsen, H., Mitchell, J. R., Croteau, D. L., & Bohr, V. A. (2014) · Cell · doi:10.1016/j.cell.2014.03.026 · Cited by 711 · see citing works
Self-citationNicotinamide riboside is uniquely and orally bioavailable in mice and humans
Trammell, S. A. J., Schmidt, M. S., Weidemann, B. J., Redpath, P., Jaksch, F., Dellinger, R. W., Li, Z., Abel, E. D., Migaud, M. E., & Brenner, C. (2016) · Nature Communications · doi:10.1038/ncomms12948 · Cited by 697 · see citing works
Characterization of the Drosophila melanogaster genome at the nuclear lamina
Pickersgill, H., Kalverda, B., de Wit, E., Talhout, W., Fornerod, M., & van Steensel, B. (2006) · Nature Genetics · doi:10.1038/ng1852 · Cited by 656 · see citing works
Neurogenesis in the Adult Brain: New Strategies for Central Nervous System Diseases
Lie, D. C., Song, H., Colamarino, S. A., Ming, G., & Gage, F. H. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121631 · Cited by 589 · see citing works
Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R. A., Kalyanasundaram, S., Bollineni, R. C., Wilson, M. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.004 · Cited by 575 · see citing works
Self-citationOxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease
Lovell, M. A., & Markesbery, W. R. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm821 · Cited by 515 · see citing works
Repair of Oxidative Damage to Nuclear and Mitochondrial DNA in Mammalian Cells
Croteau, D. L., & Bohr, V. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.41.25409 · Cited by 512 · see citing works
Self-citationFunctions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death
Herceg, Z., & Wang, Z. (2001) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(01)00111-7 · Cited by 489 · see citing works
Cheng, A., Yang, Y., Zhou, Y., Maharana, C., Lu, D., Peng, W., Liu, Y., Wan, R., Marosi, K., Misiak, M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.013 · Cited by 371 · see citing works
Self-citationLoss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle
Frederick, D. W., Loro, E., Liu, L., Davila, A., Chellappa, K., Silverman, I. M., Quinn, W. J., Gosai, S. J., Tichy, E. D., Davis, J. G., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.005 · Cited by 367 · cited 1× · see citing works
“Since decreased cellular NAD levels occur in several different tissues during normal aging, and recent studies demonstrate beneficial effects of NR on muscle strength and endurance (38, 39), we performed tests of neuromuscular function in control and NR-treated mice.”
BackgroundKashiwaya, Y., Bergman, C., Lee, J.-H., Wan, R., King, M. T., Mughal, M. R., Okun, E., Clarke, K., Mattson, M. P., & Veech, R. L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.023 · Cited by 363 · see citing works
Self-citationA high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in Cockayne syndrome
Scheibye-Knudsen, M., Mitchell, S. J., Fang, E. F., Iyama, T., Ward, T., Wang, J., Dunn, C. A., Singh, N., Veith, S., Hasan-Olive, M. M., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.005 · Cited by 352 · see citing works
Self-citationDNA repair deficiency in neurodegeneration
Jeppesen, D. K., Bohr, V. A., & Stevnsner, T. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.04.013 · Cited by 349 · see citing works
Self-citationGong, B., Pan, Y., Vempati, P., Zhao, W., Knable, L., Ho, L., Wang, J., Sastre, M., Ono, K., Sauve, A. A., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.005 · Cited by 345 · see citing works
Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice
Trammell, S. A. J., Weidemann, B. J., Chadda, A., Yorek, M. S., Holmes, A., Coppey, L. J., Obrosov, A., Kardon, R. H., Yorek, M. A., & Brenner, C. (2016) · Scientific Reports · doi:10.1038/srep26933 · Cited by 301 · cited 1× · see citing works
“NR reduced inflammation in mouse models of diabetes (61, 62).”
BackgroundWeissman, L., Jo, D.-G., Sorensen, M. M., de Souza-Pinto, N. C., Markesbery, W. R., Mattson, M. P., & Bohr, V. A. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm605 · Cited by 299 · see citing works
Self-citationBrown, K. D., Maqsood, S., Huang, J.-Y., Pan, Y., Harkcom, W., Li, W., Sauve, A., Verdin, E., & Jaffrey, S. R. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.11.003 · Cited by 277 · see citing works
Büerger, K., Zinkowski, R. P., Teipel, S. J., Tapiola, T., Arai, H., Blennow, K., Andreasen, N., Hofmann‐Kiefer, K., DeBernardis, J. F., Kerkman, D. J., et al. (2002) · Archives of Neurology · doi:10.1001/archneur.59.8.1267 · Cited by 275 · see citing works
Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment
Wang, J., Markesbery, W. R., & Lovell, M. A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03615.x · Cited by 260 · see citing works
Ryu, D., Zhang, H., Ropelle, E. R., Sorrentino, V., Mázala, D. A. G., Mouchiroud, L., Marshall, P. L., Campbell, M. D., Ali, A. S., Knowels, G. M., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf5504 · Cited by 256 · see citing works
Cued and Contextual Fear Conditioning for Rodents
Rustay, N. R., Browman, K. E., & Curzon, P. (2008) · Frontiers in neuroscience · doi:10.1201/noe1420052343.ch2 · Cited by 254 · see citing works
Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer's disease
Love, S., Barber, R., & Wilcock, G. K. (1999) · Brain · doi:10.1093/brain/122.2.247 · Cited by 254 · see citing works
Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes
Cantó, C., Sauve, A. A., & Bai, P. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.01.004 · Cited by 246 · see citing works
Ghosal, K., Vogt, D. L., Liang, M., Shen, Y., Lamb, B. T., & Pimplikar, S. W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907652106 · Cited by 245 · see citing works
Liu, D., Pitta, M., Jiang, H., Lee, J.-H., Zhang, G., Chen, X., Kawamoto, E. M., & Mattson, M. P. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.020 · Cited by 238 · see citing works
Self-citationPARP-1 involvement in neurodegeneration: A focus on Alzheimer’s and Parkinson’s diseases
Martire, S., Mosca, L., & D’Erme, M. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.04.001 · Cited by 228 · see citing works
Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease
Selkoe, D. J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16783 · Cited by 228 · see citing works
Serrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226 · see citing works
Wang, X., Hu, X., Yang, Y., Takata, T., & Sakurai, T. (2016) · Brain Research · doi:10.1016/j.brainres.2016.04.060 · Cited by 217 · see citing works
Long, A. N., Owens, K., Schlappal, A. E., Kristián, T., Fishman, P. S., & Schuh, R. A. (2015) · BMC Neurology · doi:10.1186/s12883-015-0272-x · Cited by 198 · see citing works
Genomic integrity and the ageing brain
Chow, H.-M., & Herrup, K. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4020 · Cited by 174 · see citing works
Neuroprotective Functions for the Histone Deacetylase SIRT6
Kaluski, S., Portillo, M., Besnard, A., Stein, D., Einav, M., Zhong, L., Ueberham, U., Arendt, T., Mostoslavsky, R., Sahay, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.008 · Cited by 163 · see citing works
Neuropathologic Studies of the Baltimore Longitudinal Study of Aging (BLSA)
O'Brien, R. J., Resnick, S. M., Zonderman, A. B., Ferrucci, L., Crain, B. J., Pletnikova, O., Rudow, G., Iacono, D., Riudavets, M. A., Driscoll, I., et al. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1179 · Cited by 137 · see citing works
DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes
Sýkora, P., Misiak, M., Wang, Y., Ghosh, S., Leandro, G. D. S., Liu, D., Tian, J. Y., Baptiste, B. A., Cong, W., Brenerman, B. M., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1356 · Cited by 136 · see citing works
Self-citationGenome instability in Alzheimer disease
Hou, Y., Song, H., Croteau, D. L., Akbari, M., & Bohr, V. A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.04.005 · Cited by 120 · see citing works
Self-citationNucleic acid oxidation: an early feature of Alzheimer's disease
Bradley‐Whitman, M. A., Timmons, M. D., Beckett, T. L., Murphy, M. P., Lynn, B. C., & Lovell, M. A. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12444 · Cited by 112 · see citing works
Birkmayer, J. G. D., Vrecko, C., Volc, D., & Birkmayer, W. (1993) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1993.tb00018.x · Cited by 94 · see citing works
The AAA+ ATPase, Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior
Zhang, J., Wang, Y., Chi, Z., Keuss, M. J., Pai, Y.-M. E., Kang, H., Shin, J.-H., Bugayenko, A., Wang, H., Xiong, Y., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.016 · Cited by 94 · see citing works
Self-citationCopani, A., Hoozemans, J. J. M., Caraci, F., Calafiore, M., van Haastert, E. S., Veerhuis, R., Rozemüller, A. J. M., Aronica, E., Sortino, M. A., & Nicoletti, F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2793-06.2006 · Cited by 80 · see citing works
Gait and Balance Impairments in Alzheimer Disease Patients
Muñoz, V. M., van Kan, G. A., Cantet, C., Cortes, F., Ousset, P., Rolland, Y., & Vellas, B. J. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181c78a20 · Cited by 73 · see citing works
Lee, H. J., Hong, Y., Jun, W., & Yang, S. J. (2015) · Journal of Medicinal Food · doi:10.1089/jmf.2015.3439 · Cited by 62 · see citing works
Martire, S., Fuso, A., Mosca, L., Forte, E., Correani, V., Fontana, M., Scarpa, S., Maras, B., & D’Erme, M. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151040 · Cited by 62 · see citing works
Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype
Ramamoorthy, M., Sýkora, P., Scheibye‐Knudsen, M., Dunn, C., Kasmer, C., Zhang, Y., Becker, K. G., Croteau, D. L., & Bohr, V. A. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.07.018 · Cited by 55 · see citing works
Self-citationModulation of DNA base excision repair during neuronal differentiation
Sýkora, P., Yang, J., Ferrarelli, L. K., Tian, J., Tadokoro, T., Kulkarni, A., Weissman, L., Keijzers, G., Wilson, D. M., Mattson, M. P., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.016 · Cited by 51 · see citing works
Self-citationCCR6: A Biomarker for Alzheimer's-like Disease in a Triple Transgenic Mouse Model
Subramanian, S., Ayala, P., Wadsworth, T. L., Harris, C., Vandenbark, A. A., Quinn, J. F., & Offner, H. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100852 · Cited by 50 · see citing works
Misiak, M., Greeno, R. V., Baptiste, B. A., Sýkora, P., Liu, D., Cordonnier, S. A., Fang, E. F., Croteau, D. L., Mattson, M. P., & Bohr, V. A. (2016) · Aging Cell · doi:10.1111/acel.12541 · Cited by 50 · see citing works
Self-citationDown syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging
Patterson, D. W., & Cabelof, D. C. (2011) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2011.10.001 · Cited by 48 · see citing works
Partial Reversal of Skeletal Muscle Aging by Restoration of Normal NAD + Levels
Mendelsohn, A. R., & Larrick, J. W. (2014) · Rejuvenation Research · doi:10.1089/rej.2014.1546 · Cited by 48 · see citing works
Raji, N., & Rao, K. S. (1998) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(97)00121-8 · Cited by 44 · see citing works
DNA Damage and Impairment of DNA Repair in Alzheimer's Disease
Obulesu, M., & Rao, D. M. (2010) · International Journal of Neuroscience · doi:10.3109/00207450903411133 · Cited by 40 · see citing works
The resurgence of NAD <sup>+</sup>
Guarente, L. (2016) · Science · doi:10.1126/science.aag1718 · Cited by 30 · see citing works
Wei, W., & Englander, E. W. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05644.x · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310 · see citing works
Self-citationFang, E. F., Hou, Y., Palikaras, K., Adriaanse, B. A., Kerr, J. S., Yang, B., Lautrup, S., Hasan-Olive, M. M., Caponio, D., Dan, X., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0332-9 · Cited by 1,740 · see citing works
Self-citationNAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617 · see citing works
Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States
Mattson, M. P., & Arumugam, T. V. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.011 · Cited by 1,242 · see citing works
Self-citationMolecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., Beal, M. F., Bergersen, L. H., Brinton, R. D., de la Monte, S., et al. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0072-x · Cited by 1,003 · see citing works
Self-citationTherapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.011 · Cited by 865 · see citing works
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
Self-citationPerez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426 · see citing works
Song, T., Song, X., Zhu, C., Patrick, R., Skurla, M., Santangelo, I., Green, M., Harper, D., Ren, B., Forester, B. P., et al. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101503 · Cited by 346 · see citing works
NAD metabolism: Implications in aging and longevity
Yaku, K., Okabe, K., & Nakagawa, T. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.05.006 · Cited by 269 · see citing works
Pao, P.-C., Patnaik, D., Watson, L. A., Gao, F., Pan, L., Wang, J., Adaikkan, C., Penney, J., Cam, H. P., Huang, W.-C., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16361-y · Cited by 216 · see citing works
Wang, H., Dey, K. K., Chen, P.-C., Li, Y., Niu, M., Cho, J.-H., Wang, X., Bai, B., Jiao, Y., Chepyala, S. R., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00384-6 · Cited by 210 · see citing works
Traxler, L., Herdy, J. R., Stefanoni, D., Eichhorner, S., Pelucchi, S., Szücs, A., Santagostino, A., Kim, Y., Agarwal, R. K., Schlachetzki, J. C. M., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.07.014 · Cited by 179 · see citing works
Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions
Hou, Y., Chu, X., Park, J., Zhu, Q., Hussain, M., Li, Z., Madsen, H. B., Yang, B., Wei, Y., Wang, Y., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13847 · Cited by 145 · see citing works
Self-citationMitophagy and cGAS–STING crosstalk in neuroinflammation
Zhou, X., Wang, J., Yu, L., Qiao, G., Qin, D., Yuen-Kwan Law, B., Ren, F., Wu, J., & Wu, A. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.012 · Cited by 131 · see citing works
The road ahead for health and lifespan interventions
Gonzalez-Freire, M., Diaz-Ruiz, A., Hauser, D., Martinez-Romero, J., Ferrucci, L., Bernier, M., & de Cabo, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101037 · Cited by 118 · see citing works
Contributions of DNA Damage to Alzheimer’s Disease
Lin, X., Kapoor, A., Gu, Y., Chow, M. J., Peng, J., Zhao, K., & Tang, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051666 · Cited by 117 · see citing works
Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease
Lautrup, S., Lou, G., Aman, Y., Nilsen, H., Tao, J., & Fang, E. F. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104469 · Cited by 105 · see citing works
Self-citationAlegre, G. F. S., & Pastore, G. M. (2023) · Current Nutrition Reports · doi:10.1007/s13668-023-00475-y · Cited by 101 · see citing works
Jiang, Y., Liu, Y., Gao, M., Xue, M., Wang, Z., & Liang, H. (2020) · Food & Function · doi:10.1039/c9fo01780a · Cited by 88 · see citing works
Yulug, B., Altay, O., Li, X., Hanoglu, L., Cankaya, S., Lam, S., Velioglu, H. A., Yang, H., Coskun, E., Idil, E., et al. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00336-2 · Cited by 79 · see citing works
Toward understanding genomic instability, mitochondrial dysfunction and aging
Fakouri, N. B., Hou, Y., Demarest, T. G., Christiansen, L. S., Okur, M. N., Mohanty, J. G., Croteau, D. L., & Bohr, V. A. (2019) · The FEBS Journal · doi:10.1111/febs.14663 · Cited by 77 · see citing works
Self-citationBST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities
Yaku, K., Palikhe, S., Izumi, H., Yoshida, T., Hikosaka, K., Hayat, F., Karim, M., Iqbal, T., Nitta, Y., Sato, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27080-3 · Cited by 76 · see citing works
Ear, P. H., Chadda, A., Gumusoglu, S. B., Schmidt, M. S., Vogeler, S., Malicoat, J., Kadel, J., Moore, M. M., Migaud, M. E., Stevens, H. E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.007 · Cited by 72 · see citing works
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Hikosaka, K., Yaku, K., Okabe, K., & Nakagawa, T. (2021) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1637504 · Cited by 62 · see citing works
Molecular mechanisms of mitophagy and its roles in neurodegenerative diseases
Li, X., Huang, L., Lan, J., Feng, X., Li, P., Wu, L., & Peng, Y. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2020.105240 · Cited by 57 · see citing works
DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease
Wang, H., Lautrup, S., Caponio, D., Zhang, J., & Fang, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136748 · Cited by 55 · see citing works
Self-citationLloret, A., & Beal, M. F. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02809-1 · Cited by 52 · see citing works
Harlan, B. A., Pehar, M., Killoy, K. M., & Vargas, M. R. (2019) · The FASEB Journal · doi:10.1096/fj.201802752r · Cited by 50 · see citing works
Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism
Rivell, A., & Mattson, M. P. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.08.006 · Cited by 50 · see citing works
Self-citationNovel Nutraceutical Compounds in Alzheimer Prevention
Maccioni, R. B., Calfío, C., González, A., & Lüttges, V. (2022) · Biomolecules · doi:10.3390/biom12020249 · Cited by 45 · see citing works
Metabolic reprogramming: a bridge between aging and tumorigenesis
Drapela, S., Ilter, D., & Gomes, A. P. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13261 · Cited by 41 · see citing works
Histone Deacetylases 1 and 2 in Memory Function
Pao, P.-C., & Tsai, L.-H. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00775 · Cited by 34 · see citing works
Xiong, W., Xu, K., Sun, J. K.-L., Liu, S., Zhao, B., Shi, J., Herrup, K., Chow, H.-M., Lu, L., & Li, J. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00270-7 · Cited by 17 · see citing works
“After 10 min, the mice were returned to their housing cages (Hou, 2018; Iaccarino et al, 2016).”
NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease
Fan, F., Joshi, P., Liu, X., Kotturu, S. K., Abiola, M., Liu, Q., & Lou, X. (2025) · doi:10.64898/2025.12.21.695860
- Authors
- Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D. L., Zavala, E., Zhang, Y., Moritoh, K., O’Connell, J. F., Baptiste, B. A., Stevnsner, T. V., Mattson, M. P., & Bohr, V. A.
- Affiliations
- National Institutes of Health (US)
- Aarhus University (DK)
- University of Copenhagen (DK)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-02-05
- Volume
- 115
- Issue
- 8
- Pages
- E1876-E1885
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5828618
- OpenAlex
- W2793585092
- Cited by
- 472
- References
- 71
- Citations by year
- 2026: 50 · 2025: 57 · 2024: 56 · 2023: 58 · 2022: 58 · 2021: 67 · 2020: 70 · 2019: 39 · 2018: 17
- FWCI
- 33.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute on Aging (ZIA AG00073517)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, NAD+ supplementation, nicotinamide riboside, DNA repair deficiency, DNA damage response, phosphorylated tau, neuroinflammation, neuronal apoptosis, SIRT3, brain energy metabolism, synaptic dysfunction, hippocampal synaptic plasticity, cognitive impairment, amyloid-beta
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, DNA Damage, Gene Expression Regulation, Male, Mice, Transgenic, NAD, Niacinamide, Pyridinium Compounds, tau Proteins, Sirtuins, Mice, Neurogenesis, Sirtuin 3, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
